Genetic variation in the immune response influences susceptibility to infection (e.g., HIV) and autoimmune diseases, highlighting a delicate balance in discriminating between response to foreign antigen and tolerance to self antigens. One of the most clinically important relationships between gene variation and the immune response involves the role of host factors in HIV: large epidemiological cohort studies have identified ten common alleles (eight genes) that are associated with transmission of HIV and rate of progression to AIDS. These alleles explain only a small fraction of the clinical heterogeneity in HIV, however, suggesting that additional genes influence the risk of developing HIV/AIDS. To study genetic regulation of complex immune system responses, this grant proposes to systematically explore genetic variation in two distinct subgroups of candidate genes for a contribution to HIV infection and progression to AIDS: genes that regulate the production of beta-chemokines and genes associated with autoimmune disease. First, levels of the beta-chemokines RANTES, MIP1-alpha, and MIP1-beta have been shown to be elevated in individuals resistant to HIV infection and those HIV-positive patients who progress slowly to AIDS. What has not been extensively studied is whether genetic variation within genes regulating the production of beta-chemokines may contribute to the clinical heterogeneity of HIV/AIDS. Second, prior studies have shown that two genes associated with HIV/AIDS, HLA and CCR5, also influence risk of autoimmune disease. This suggests that other genes known to influence autoimmunity (e.g., NOD2/CARD15, CTLA4, and the 5q31 cytokine gene cluster) might also alter response to HIV/AIDS. Thus, this grant proposes two Specific Aims. 1) To perform genetic association studies with 25 genes that regulate the production of RANTES, MIP1-alpha, and MIP1-beta in a cohort of approximately 3500 HIV/AIDS patients; and 2) To perform genetic association studies with three loci, NOD2/CARD15, CTLA4, and 5q31 cytokine gene cluster, in a cohort of approximately 3500 HIV/AIDS patients. These studies hope to identify novel genes that influence susceptibility to HIV/AIDS, thereby providing insight into HIV/AIDS pathogenesis and, ultimately, improving patient care.